In America, lung cancer and melanoma are predicted to be the second and seventh most prevalent cancers for the year 2002, respectively (American cancer Society, Inc., 2002). Moreover, the all stage five-year relative survival rate between 1992–1997 for lung cancer in this country is only about 15%. On the other hand, although the five-year survival rate for all stage melanoma patients is relatively high at 89%, this rate drops sharply to approximately 12% when disease undergoes transformation into malignancy and metastasizes to distant sites in the body. Therefore, the low survival rates in these diseases call for newer cancer therapeutic approaches to be implemented.
In recent years there has been a growing interest in the development and application of active specific immunotherapy for the treatment of malignant diseases, in part due to the limited success of conventional therapy (see Giaccone et al., Cancer Chemotherapy and Biological Response Modifiers Annual 19, 2001). For developing tumor vaccines of melanoma, two major approaches have been used: 1) immunizations with whole tumor cell extracts or irradiated tumor cells (Takashi, et al. 1999; Hsueh, 2001); 2) immunizations with melanoma associated antigens such as MART-1 or gp100 (Chianese-Bullock, et al. 2002). Several researchers have considered the T cell and/or antibody-based immunotherapeutic approaches in patients with malignant diseases. The molecular characterization of T cell and/or antibody defined tumor associated antigen (TAA) has providded investigators with well-defined moieties to immunize patients with malignancies and to monitor the elicited immune response.
It has been reported that in humans, the large majority of tumor antigens are non-mutated self-antigens. They are likely to be expressed at a higher level by malignant cells than by normal cells because of systemic gene deregulation associated with the cell transformation process. Therefore development of strategies effective in inducing a strong immune response against self-TAA represents one of the major challenges facing immunologists.
One of the approaches used is the administration of anti-idiotypic antibodies. However, the majority of anti-idiotypic (anti-id) antibodies are of xenogenic origin, most being mouse monoclonal antibodies. As expected, administration of xenogenic anti-id antibodies induces high titer antibodies to the constant and variable regions of the immunizing antibody. Further, it has been reported that immunization with anti-id antibodies elicits humoral immunity, but not induced HLA class I antigen restricted TAA mimicty in most of the antigenic systems analyzed. In addition, it is also reported that there is low reactivity of the elicited antibodies with the original TAA. Accordingly, there continues to be need in the field of immunotherapy to develop novel approaches to stimulate an immune response against TAAs.
GD3 ganglioside is a self-glycolipid antigen highly expressed in human melanoma lesions and lung cancer cells compared to most normal tissues. Anti-GD3 monoclonal antibodies have been shown to effectively mediate lysis of GD3+ melanoma cells by complement and antibody-dependent mechanisms. Furthermore, antiGD3 monoclonal antibody may affect the biology of melanoma cells and can lead to inhibition of melanoma cell growth. These findings suggest that generation of immunity that specifically targets GD3 may have a beneficial effect on the clinical course of the disease by mediating destruction of GD3+ melanoma cells. However, development of active immunotherapy has been hampered by the unresponsiveness of patients' immune system to GD3.
In previous studies, peptide mimics have been generated and shown to induce specific immune responses against several antigens, including carbohydrate antigens such as Lewis antigens and S. pneumoniae serotype 4 capsular polysaccharide (Lesinski et al., 2001; Luo et al., 2000). In addition, clinical trials have already begun based on another kind of antigen mimic to GD3, an anti-idiotypic antibody BEC2 (Chapman et al., 1994; McCaffer et al., 1996; Yao et al., 1999). Immunization with BEC2 have been associated with induction of immune responses specifically targeted against GD3 in melanoma (Yao et al., 1999) and small cell lung cancer patients (Grant et al., 1999). Although GD2/GD3 peptide mimics have been isolated with an anti-GD2/GD3 antibody ME36.1, the antigenicity of these peptides was not demonstrated (Qiu et al., 1999), nor their ability to generate antisera that can bind to GD3 bearing cells. Accordingly, there continues to be a need to further identify and develop peptide mimics of tumor associated antigens useful for generating an immune response.